A New Gene Editing Technique Has Treated Its First Human Disease

Curing sickle cell anemia, without transplant donors, by changing our own DNA.

No, that’s “crisper,” not “CRISPR.” I still think of lettuce when I hear the gene-editing technique’s name. Photo by Jef Wright on Unsplash

Doctors are taking the first steps towards solving a massive source of disease that, until now, has seemed out of reach. Our genes, the instructions inside of our cells that dictate how each one of us works, why each one of us is unique, have been untouchable — until now.

Britain’s medicines regulator has just approved the first gene editing treatment to help fix a lifelong disease.

The editing treatment, a technique called CRISPR, has been around for several years. (Its discoverers won a Nobel Prize for it in 2020.) But until now, it’s not been approved by a governing body for medical use in humans.

Sickle cell anemia is a genetic disease; patients are born with faulty genes. The new CRISPR gene editing treatment fixes this gene, but there are still dangers of side effects. These side effects limit doctors from targeting all genetic ailments — for now.

Sickle cell anemia = badly shaped red blood cells

You are full of blood, and that blood is red because of iron-rich red blood cells. Slightly less than half of your blood, by volume, is red blood cells. (The rest is mostly water, and a small fraction of other, more specialized cells.)

Normally, red blood cells are shaped like little donuts. They’re quite simple; they don’t contain any DNA, and they’re basically squishy little bags full of a protein called hemoglobin, which carries oxygen around our body.

*If this were red, with fewer sprinkles, it would look very much like a red blood cell. Photo by Fahim mohammed on Unsplash*

Because red blood cells are just flexible little baggies of hemoglobin, they can’t reproduce. Stem cells, located inside the marrow of our bones, constantly spawn new red blood cells. The fresh red blood cells split off the larger stem cell and leave the bones to journey throughout the body in the bloodstream.

In some people, the hemoglobin protein inside their red blood cells has a slightly different structure, because of a mutation (a slightly different DNA sequence) in the gene that produces hemoglobin. This mutated protein will become sticky when there’s not a lot of oxygen, making clumps.

As a result, some of the red blood cells in these people will become hard, ragged, and spiky, looking a bit like tiny sickles. These hard, ragged red blood cells break down faster than regular red blood cells and can also get stuck in narrow blood vessels, creating traffic jams called clots.

People born with this sickle cell mutation usually start showing symptoms in early childhood, around 6 months old. They’ll go through semi-regular flare-ups with a range of negative symptoms including pain, organ damage, and other issues caused by bouts of reduced oxygen availability. When the blood can’t distribute enough oxygen to the rest of the body, it’s called anemia.

Changing how we treat sickle cell anemia by changing our DNA

Until now, the best treatment for sickle cell anemia has been to try to add in some healthy red blood cells by transplanting in new stem cells. We transplant some new bone marrow into the patient, the bone marrow produces regular donut-shaped squishy red blood cells, and there’s less chance of sickle-induced traffic jams.

However, bone marrow transplants are difficult to arrange. The donor has to be a nearly identical genetic match to the patient; otherwise, the patient’s immune system will fight back and destroy the transplanted bone marrow stem cells. The transplant process is also painful, requires extended stays in a hospital, and usually requires that patients take immune system suppressing drugs for months to years after the transplant.

Here’s where CRISPR comes in. What if, instead of replacing the bad stem cells in the patient, we repaired them, with a genetics discovery that sounds like a weird lettuce-themed startup?

What is CRISPR, anyway?

CRISPR is the name for a genetic technology that, at its simplest form, is a pair of scissors for cutting DNA.

DNA is long, and there’s tons of it. In an organism, all of the DNA is referred to as a genome, while individual little stretches of DNA are referred to as genes. Each gene is the instructions for how to make a protein, and the genome is a collection of genes + filler DNA. In humans, the genome is spread over 23 different collections, each called a chromosome.

(Analogy time: think of the genome as a book-bound set of cookbooks. Each recipe is a gene, and each book in the set is a chromosome. Each recipe also has some introductory text that talks about where the recipe came from, how it’s served, and other useful tertiary info; that’s the filler DNA that separates genes from each other.)

Only about 1% of the genome is actual genes, the DNA stretches that specify the recipe for the proteins that make up the human body. The other 99% is a Wild West of junk sequences, repeated strips that serve as spacers, and other sequences that seem to control whether genes are turned on or off, and how activated they are.

The challenge is that, because there’s so much DNA, it’s very hard to make changes to one spot without accidentally hitting a bunch of other spots that you don’t want to change. Any method to edit the DNA must be incredibly specific.

CRISPR is a huge innovation because it’s a pair of incredibly specific scissors for cutting DNA. It makes a cut at the spot we want, and (usually) not in other spots we don’t want.

Bringing it back to sickle cell anemia; a new medicine made by Vertex Pharmaceuticals, called Casgevy, uses a pair of tailored CRISPR scissors to cut, and then fix, the broken gene that makes mutant hemoglobin.

How does Casgevy work?

With the new treatment, the process goes:

The sickle cell anemia patient takes a dose of chemotherapy to temporarily reduce the strength of their immune system.
Doctors surgically take a sample of stem cells (bone marrow) from the patient.
In the laboratory, scientists treat the cells with Casgevy, using CRISPR to modify them to produce proper hemoglobin.
After confirming that the cells are producing the proper hemoglobin protein, they get surgically infused back into the patient.
The patients are monitored to determine if they begin producing hemoglobin that isn’t sticky and sickle shaped (“regular” hemoglobin).

This is still not a fun process. Chemotherapy is not a pleasant process, and the patient still needs to have 2 surgeries; one to extract the stem cells, and the second to insert them back in.

However, there are some big advantages.

First, this method doesn’t require any donor. Patients are treated with their own, modified cells.

Second, this approach poses an incredibly small risk of rejection. In normal transplants, the patient has to take immune system suppressing drugs, often for years afterward, to help stop their own immune system from destroying the transplanted organ as an invader. With this approach, since it’s the patient’s own cells being transplanted back in, there’s no risk of setting off immune alarms.

Finally, there’s still a check on this process. Because the extracted stem cells are modified in a Petri dish in a laboratory, doctors can make sure that the CRISPR approach worked, and that the cells haven’t picked up any negative mutations, before transplanting them back in.

That last point is a big reason why we aren’t approving gene therapies right and left. There’s still a risk with any gene modification method, including CRISPR, of hitting the wrong areas of the DNA and causing negative mutations, or even cancer. The gene therapy methods that are most likely to be approved are ones that specifically modify cells once they’ve been removed from the rest of our body.

Casgevy, the newly approved treatment for sickle cell anemia, is a first-of-its-kind use of CRISPR gene modification to alter the patient’s own misbehaving stem cells. It modifies the patient’s own (extracted) cells to fix their broken hemoglobin gene, letting the patient produce their own non-sickled blood.

There are almost certainly going to be more CRISPR-driven therapies on the horizon. It’s a versatile method for fixing many different diseases, caused by mutations in our genes, that were previously unfixable.

We’re still a long way from seeing approved methods that use CRISPR inside the patient’s own body, so not every disease could potentially be treated this way. Still, this is an incredible use of gene-editing molecular technology for treating a health condition.